The recognition that prostate cancer clusters within families has led many research teams including our own to collect families with multiple cases of prostate cancer for linkage studies. Unfortunately, despite the collection and analysis of a large number of such families, the major genes that contribute to inherit prostate cancer susceptibility have been difficult to fully characterize. At least eight loci have been proposed and further studies are now required to determine the most clinically important prostate cancer predisposition genes. The University of Michigan Prostate Cancer Genetics Project (PCGP) was established in 1995 as a family based study of inherited prostate cancer susceptibility. A genome wide linkage scans was recently completed using 176 multiplex PCGP families, which has implicated several new genomic regions for additional study. The strongest evidence for prostate cancer linkage was on chromosome 17 adjacent to the BRCA1 gene. Mutations in the BRCA1 gene have been shown to increase the risk of breast and ovarian cancer in women as well as prostate cancer in men, however BRCA1 mutations have not been previously identified in prostate cancer families. To further characterize the role of BRCA1 in hereditary prostate cancer and to define other prostate cancer susceptibility genes and their associated clinical syndromes, the following three Specific Aims are proposed: 1) To evaluate the role of the breast cancer gene BRCA1 as a prostate cancer susceptibility gene in PCGP families, 2) to localize and characterize candidate prostate cancer susceptibility genes in PCGP families, 3) To identify prostate cancer susceptibility genes that specifically influences the risk of developing clinically aggressive prostate cancer. Completion of these aims will improve our understanding of the genes that predispose men to prostate cancer as well as the clinical syndromes associated with specific gene mutations. Ultimately, this information may have clinical utility to identify those men at highest risk of prostate cancer who may benefit from early detection and/or chemoprevention strategies.